1. Field of the Invention
The present invention relates to methods for preventing and treating Alzheimer's disease (AD).
2. Description of Related Art
Amyloid-β peptide (Aβ) plays a central role in the neuropathology of Alzheimer's disease (AD) (Roher et al 1993: “β-Amyloid-(1-42) is a major component of cerebrovascular amyloid deposits: Implications for the pathology of Alzheimer disease” PNAS 90:10836). Familial forms of the disease have been linked to mutations in the amyloid precursor protein (APP) and the presenilin genes. Disease-linked mutations in these genes result in increased production of the 42-amino acid form of the peptide (Aβ42), which is the predominant form found in the amyloid plaques of Alzheimer's disease. An animal model for the disease is commercially available. The PDAPP transgenic mouse, which over-expresses mutant human APP (in which the amino acid at position 717 is F instead of V), progressively develops many of the neuropathological hallmarks of Alzheimer's disease in an age- and brain-dependent manner (Games et al 1995: “Alzheimer-type neuropathology in transgenic mice overexpressing V717β-amyloid precursor protein” Nature 373:523).
Vaccination studies with a “normal”, not mimotope-based vaccine have already been performed. Transgenic animals were immunized with aggregated Aβ42, either before the onset of AD-type neuro-pathologies (6 weeks) or at an older age (11 months): Immunization of young animals prevented the development of plaque formation, neuritic dystrophy and astrogliosis. Treatment of older animals markedly reduced AD-like neuropathologies. This experimental vaccination approach induced the development of antibodies against Aβ42 able to cross the blood-brain barrier and at-tack amyloid plaques (Schenk et al 1999: “Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PD-APP mouse” Nature 400:173). The plaques are subsequently removed by several mechanisms, including Fc-receptor mediated phagocytosis (Bard et al 2000: “Peripherally administered antibodies against amyloid β-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease” Nature Med 6:916). This vaccine was also able to delay memory deficits (Janus et al 2000: “Aβ peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease” Nature 408:979).
A highly promising immunization therapy for AD has been in clinical trials since late 1999. Immunization is presumed to trigger the immune system to attack the plaques and clear these deposits from the affected human brain, although the precise mechanism underlying needs to be characterized in more detail.
These clinical trials were conducted by the pharmaceutical company Elan in conjunction with its corporate partner, American Home Products (therapeutic vaccine AN-1792, QS21 as adjuvant). Phase I trials were successfully completed in 2000. Phase II trials were begun late 2001 to test efficacy in a panel of patients with mild to moderate AD.
Now these phase II trials have been permanently discontinued due to neuroinflammation in several patients (Editorial 2002 “Insoluble problem?” Nature Med 8:191). The symptoms included aseptic meningoencephalitis leading to the immediate halt of these world-wide trials. In the worst case scenario, affected patients will be shown to have mounted an autoimmune response—a risk inherent in many immunotherapies. Autoimmune complications could have been anticipated given the ubiquity of APP, which of course bears antigenic determinants in common with its proteolytic product. More recently, additional studies concentrated on the nature of aggregated Aβ42 immunization-induced antibodies (in humans and mice) revealing that most antibodies recognize a small domain between amino acid 4 and 10 of Aβ42 (Aβ4-10). The mouse antibodies were able to block Afl fibrillogenesis and disrupted pre-existing Aβ fibers (McLaurin et al 2002: “Therapeutically effective antibodies against amyloid-β peptide target amyloid-β residues 4-10 and inhibit cytotoxicity and fibrillogenesis” Nature Med 8:1263). Of note, the human antibodies do not react with APP exposed on the surface of cells or any other non-aggregated proteolytic product of the precursor (Hock et al 2002: “Generation of antibodies specific for β-amyloid by vaccination of patients with Alzheimer disease” Nature Med 8:1270).
A clear difference was observed between human and mouse sera: In contrast to human antibodies, mouse antibodies detect monomeric, oligomeric, and fibrillar Aβ. This is of importance and may be a prerequisite for the therapeutic potency since evidence is accumulating that small oligomers of Aβ, which are not recognized by human anti-AO, are the major toxic players in the disease (Walsh et al 2002: “Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo” Nature 416:535). Thus, a potential new strategy is the immunization with a vaccine containing β-amyloid amino acids 4-10 (instead of aggregated Aβ42). Despite unknown efficacy this strategy may also face autoimmune problems since patients shall be directly immunized with a (linear B cell) “self” epitope.
Despite these disappointing developments in recent AD vaccination strategies, an Aβ vaccine is still regarded as the most promising way for combatting AD. However, there is an urgent need for improvements and new strategies in AD vaccination. Especially, such a vaccine should not induce autoreactive T and/or B. cells.